Cannabinoids inhibit HIV-1 Gp120-mediated insults in brain microvascular endothelial cells.
HIV-1 infection has significant effect on the immune system as well as on the nervous system. Breakdown of the blood-brain barrier (BBB) is frequently observed in patients with HIV-associated dementia (HAD) despite lack of productive infection of human brain microvascular endothelial cells (HBMEC). Cellular products and viral proteins secreted by HIV-1 infected cells, such as the HIV-1 Gp120 envelope glycoprotein, play important roles in BBB impairment and HIV-associated dementia development. HBMEC are a major component of the BBB. Using cocultures of HBMEC and human astrocytes as a model system for human BBB as well as in vivo model, we show for the first time that cannabinoid agonists inhibited HIV-1 Gp120-induced calcium influx mediated by substance P and significantly decreased the permeability of HBMEC as well as prevented tight junction protein down-regulation of ZO-1, claudin-5, and JAM-1 in HBMEC. Furthermore, cannabinoid agonists inhibited the transmigration of human monocytes across the BBB and blocked the BBB permeability in vivo. These results demonstrate that cannabinoid agonists are able to restore the integrity of HBMEC and the BBB following insults by HIV-1 Gp120. These studies may lead to better strategies for treatment modalities targeted to the BBB following HIV-1 infection of the brain based on cannabinoid pharmacotherapies.
Lu
Tzong-Shi
TS
Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Avraham
Hava Karsenty
HK
Seng
Seyha
S
Tachado
Souvenir D
SD
Koziel
Henry
H
Makriyannis
Alexandros
A
Avraham
Shalom
S
D015526:AIDS Dementia Complex / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control / Q000821:virology; D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001095:Arachidonic Acids / Q000494:pharmacology* / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology / Q000821:virology*; D063385:Cannabinoid Receptor Modulators / Q000819:agonists / Q000494:pharmacology* / Q000502:physiology; D002219:Carbamates / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D018920:Coculture Techniques; D063388:Endocannabinoids; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology / Q000821:virology*; D005989:Glycerides / Q000494:pharmacology* / Q000502:physiology; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors* / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D019380:Anti-HIV Agents; D001095:Arachidonic Acids; D001549:Benzamides; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D063388:Endocannabinoids; D005989:Glycerides; D015699:HIV Envelope Protein gp120; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C094503:glyceryl 2-arachidonate